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Updated: Dec 6, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Targeting Dormant Ovarian Cancer Cells In Vitro and in an In Vivo Mouse Model of Platinum Resistance
Zhiqing Huang1,2, Eiji Kondoh2,3, Zachary R Visco1,2
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University Medical Center, Durham, North Carolina.
Abstract:
Spheroids exhibit drug resistance and slow proliferation, suggesting involvement in cancer recurrence. The protein kinase C inhibitor UCN-01 (7-hydroxystaurosporine) has shown higher efficacy against slow proliferating and/or quiescent ovarian cancer cells. In this study, tumorigenic potential was assessed using anchorage-independent growth assays and spheroid-forming capacity, which was determined with ovarian cancer cell lines as well as primary ovarian cancers. Of 12 cell lines with increased anchorage-independent growth, 8 formed spheroids under serum-free culture conditions. Spheroids showed reduced proliferation (P < 0.0001) and Ki-67 immunostaining (8% vs. 87%) relative to monolayer cells. Spheroid formation was associated with increased expression of mitochondrial pathway genes (P ≤ 0.001) from Affymetrix HT U133A gene expression data. UCN-01, a kinase inhibitor/mitochondrial uncoupler that has been shown to lead to Puma-induced mitochondrial apoptosis as well as ATP synthase inhibitor oligomycin, demonstrated effectiveness against spheroids, whereas spheroids were refractory to cisplatin and paclitaxel. By live in vivo imaging, ovarian cancer xenograft tumors were reduced after primary treatment with carboplatin. Continued treatment with carboplatin was accompanied by an increase in tumor signal, whereas there was little or no increase in tumor signal observed with subsequent treatment with UCN-01 or oltipraz. Taken together, our findings suggest that genes involved in mitochondrial function in spheroids may be an important therapeutic target in preventing disease recurrence.
Insights
Ovarian cancer spheroids, resistant to standard therapies, show reduced proliferation and increased mitochondrial gene expression. The drug UCN-01 effectively targets these spheroids, suggesting a new therapeutic strategy for preventing cancer recurrence.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Spheroids, characterized by drug resistance and slow proliferation, are implicated in ovarian cancer recurrence.
- The protein kinase C inhibitor UCN-01 demonstrates efficacy against quiescent ovarian cancer cells.
Purpose of the Study:
- To assess the tumorigenic potential of ovarian cancer spheroids.
- To investigate the therapeutic efficacy of UCN-01 and other agents against these spheroids.
- To identify molecular targets within spheroids for preventing disease recurrence.
Main Methods:
- Anchorage-independent growth assays and spheroid-forming capacity were evaluated in ovarian cancer cell lines and primary tumors.
- Proliferation and Ki-67 immunostaining were compared between spheroids and monolayer cells.
- Gene expression analysis focused on mitochondrial pathway genes.
- Therapeutic efficacy was tested using UCN-01, oligomycin, cisplatin, paclitaxel, carboplatin, and oltipraz in vitro and in vivo xenograft models.
Main Results:
- Eight of twelve cell lines with increased anchorage-independent growth formed spheroids.
- Spheroids exhibited significantly reduced proliferation and Ki-67 expression compared to monolayer cells.
- Spheroid formation correlated with increased expression of mitochondrial pathway genes.
- UCN-01 and oligomycin were effective against spheroids, while cisplatin and paclitaxel were not.
- In vivo, UCN-01 showed potential in preventing tumor regrowth after carboplatin treatment.
Conclusions:
- Ovarian cancer spheroids possess distinct characteristics, including reduced proliferation and altered mitochondrial gene expression, contributing to therapeutic resistance.
- UCN-01 demonstrates significant efficacy against spheroids, highlighting its potential as a targeted therapy.
- Targeting genes involved in mitochondrial function within spheroids may offer a promising strategy to prevent ovarian cancer recurrence.
